PTSD Risk in Women Tied to Genetics

by John Gever John Gever Senior Editor, MedPage Today
February 23, 2011

Action Points

Note that this study suggests that changes in a particular pathway that may be estrogen regulated are involved in abnormal stress responses underlying PTSD and may help to explain why women might be more likely than men to develop PTSD.

Point out that even if the gene variant is only a biomarker, it could still help in the search for individuals at high risk for PTSD and thus aid in the search for appropriate therapeutic approaches to the disorder.

A common gene variant was associated with a nearly doubled likelihood of posttraumatic stress disorder (PTSD) in at-risk urban women -- but not in otherwise similar men, researchers said.

The affected gene encodes a receptor protein believed to mediate stress responses, and is also modulated by estrogen signaling, according to Kerry Ressler, MD, PhD, of Emory University in Atlanta, reporting in the Feb. 24 issue of Nature.

Heavily traumatized civilian women with two copies of a specific single nucleotide polymorphism (SNP) in the ADCYAP1R1 gene were more likely to show PTSD with an odds ratio of 1.66 (95% CI 1.32 to 2.09) relative to similar women without the condition, Kessler and colleagues found.

The same SNP -- called rs2267735, substituting a cytosine base for a guanine -- in men exposed to fearful situations showed no association with PTSD, the researchers also found (OR 0.95, 95% CI 0.71 to 1.27).

The authors did point out, however, that women are more likely to develop PTSD than men, and this discrepancy may relate to the modulation of the receptor pathway by estrogen.

Nearly 40% of women in the study had the CC genotype, carrying two copies of the risk-associated SNP.

In that group, an average of 15 PTSD symptoms were identified clinically, compared with 11 in individuals with the CG or GG genotypes (P<0.05).

About one-third of the 763 women in the study were diagnosed with PTSD.

Other researchers contacted by MedPage Today and ABC News said the results were promising but needed replication in larger and different samples.

"This study was done on chronically ill patients, those with both chronic medical and chronic psychological comorbidities, so it's difficult to know if the signaling is from PTSD or from their comorbidities," said Charles Marmar, MD, of NYU Langone Medical Center in New York City, in an e-mail. "There's a need for replication in a younger, healthier population with more recent trauma exposure."

Judith A. Myers-Walls, PhD, of Purdue University in West Lafayette, Ind., also noted that the methodology left some questions unanswered.

"The data were collected after the PTSD symptoms were identified, so it is not clear whether the stress reaction itself created the changes in physiology or they existed before the exposure to the stressful situation," she said in an e-mail.

Among the individual PTSD symptoms, hyperarousal was the one most strongly associated with the CC genotype. After controlling for trauma history, age, and race, women with the CC genotype had mean hyperarousal scores of about 5.2, compared with 3.9 among women with at least one G allele (P=0.0008).

Women with the CC genotype also showed exaggerated startle responses.

All these effects were completely confined to women in the study. For the genetic research, Ressler and colleagues initially analyzed a group of 503 women and 295 men. They then confirmed the findings in a replication set of 260 women and 179 men -- also drawn from the same population of trauma-exposed city dwellers but enrolled later and interviewed by different staff.

Most of the associations reported in the Nature paper were calculated from both samples combined.

Ressler and colleagues actually started out investigating the role of a protein called PACAP, the pituitary adenylate cyclase-activating polypeptide, which earlier studies had linked to cellular stress responses. PACAP is the natural ligand for the receptor encoded by ADCYAP1R1.

Blood levels of the peptide were significantly associated with PTSD symptom counts, startle reflexes, and other measures of fear physiology, the researchers found -- but again only in women.

Ressler and colleagues also found that expression of an ADCYAP1R1 homologue in rodents was increased with estrogen replacement and with fear conditioning -- supporting a role for the gene and its protein product, the PAC1 receptor, in handling stress.

The researchers suggested that PACAP had potential clinical application as a biomarker of active PTSD, whereas ADCYAP1R1 genotype might be used to identify individuals most at risk for PTSD following trauma.

More study of the pathway may also reveal therapeutic targets for PTSD treatments, Ressler and colleagues indicated.

In an accompanying commentary published in Nature, Murray B. Stein, MD, of the University of California San Diego, suggested it would be premature to put the study's findings into clinical use immediately.

In addition to replicating the findings, he wrote, "more must be learned about the relationship between PACAP levels in peripheral blood and cerebrospinal fluid, and, particularly, in the regions of the brain that modulate the fear response."

Stein also called for studies of other genetic factors previously linked to PTSD and how they may be related to ADCYAP1R1.

Steven P. Hamilton, MD, PhD, of the University of California San Francisco, told MedPage Today and ABC News in an e-mail that the study's genetic findings were clearly important, at least as a starting point.

"So far, we have only a minimal understanding of the genetic factors influencing PTSD, so this finding is a promising advance, and suggests that more genetic research into anxiety disorders is warranted," said Hamilton.

This article was developed in collaboration with ABC News.

The study was funded primarily by the National Institutes of Health. Some authors also received salary support from other government and foundation sources.

Study authors and Stein declared they had no relevant financial interests.

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